chr8-32595840-G-A

Variant names:

• chr8-32595840-G-A
• rs3924999
• NM_013964.5:c.113G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_013964.5(NRG1):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,602,172 control chromosomes in the GnomAD database, including 132,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (9549 hom., cov: 32)
  • Exomes 𝑓: 0.40 (122776 hom.)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.37
• Publications: 115 publications found

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

• schizophrenia 6

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0896198E-6).
• BP6: Variant 8-32595840-G-A is Benign according to our data. Variant chr8-32595840-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059329.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 2 of 12	NP_039258.1	Q02297-1
	NRG1	NM_013956.5		c.113G>A	p.Arg38Gln	missense	Exon 2 of 13	NP_039250.2	Q02297-6
	NRG1	NM_013957.5		c.113G>A	p.Arg38Gln	missense	Exon 2 of 12	NP_039251.2	Q02297-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 2 of 12	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 2 of 13	ENSP00000287842.4	Q02297-6
	NRG1	ENST00000356819.7	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 2 of 12	ENSP00000349275.6	Q02297-7

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48749 AN: 151506 Hom.: 9560 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.358

GnomAD2 exomes AF: 0.399 AC: 98691 AN: 247262 AF XY: 0.401

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.777

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.402 AC: 583779 AN: 1450548 Hom.: 122776 Cov.: 35 AF XY: 0.402 AC XY: 289904 AN XY: 721876

African (AFR) AF: 0.0996 AC: 3257 AN: 32716

American (AMR) AF: 0.431 AC: 18688 AN: 43334

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9000 AN: 25532

East Asian (EAS) AF: 0.774 AC: 30624 AN: 39546

South Asian (SAS) AF: 0.410 AC: 34938 AN: 85318

European-Finnish (FIN) AF: 0.342 AC: 17903 AN: 52356

Middle Eastern (MID) AF: 0.339 AC: 1921 AN: 5666

European-Non Finnish (NFE) AF: 0.401 AC: 443467 AN: 1106460

Other (OTH) AF: 0.402 AC: 23981 AN: 59620

GnomAD4 genome AF: 0.321 AC: 48739 AN: 151624 Hom.: 9549 Cov.: 32 AF XY: 0.325 AC XY: 24041 AN XY: 74084

African (AFR) AF: 0.112 AC: 4647 AN: 41308

American (AMR) AF: 0.370 AC: 5639 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1205 AN: 3472

East Asian (EAS) AF: 0.771 AC: 3982 AN: 5162

South Asian (SAS) AF: 0.426 AC: 2033 AN: 4770

European-Finnish (FIN) AF: 0.348 AC: 3665 AN: 10524

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26463 AN: 67850

Other (OTH) AF: 0.358 AC: 753 AN: 2104

Alfa AF: 0.378 Hom.: 53517

Bravo AF: 0.319

TwinsUK AF: 0.406 AC: 1505

ALSPAC AF: 0.414 AC: 1595

ESP6500AA AF: 0.133 AC: 586

ESP6500EA AF: 0.396 AC: 3404

ExAC AF: 0.390 AC: 47361

Asia WGS AF: 0.547 AC: 1902 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NRG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.042
Sift	Benign	0.044	D
Sift4G	Benign	0.074	T
Polyphen		0.70	P
Vest4		0.069
MPC		0.28
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.081
gMVP		0.32
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3924999; hg19: chr8-32453358; COSMIC: COSV55177787;